FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.
Carlos J Diaz OstermanDuygu OzmadenciElizabeth G KleinschmidtKristin N TaylorAllison M BarrieShulin JiangLisa M BeanFlorian J SulzmaierChristine JeanIsabelle TancioniKristen AndersonSean UryuEdward A CordascoJian LiXiao Lei ChenGuo FuMarjaana OjalillPekka RappuJyrki HeinoAdam M MarkGuorong XuKathleen M FischVihren N KolevDavid T WeaverJonathan A PachterBalázs GyőrffyMichael T McHaleDenise C ConnollyAlfredo MolinoloDwayne G StupackDavid D SchlaepferPublished in: eLife (2019)
Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.
Keyphrases
- cell migration
- copy number
- genome wide
- high grade
- dna repair
- cell proliferation
- epithelial mesenchymal transition
- stem cells
- single cell
- mitochondrial dna
- transcription factor
- endothelial cells
- dna damage
- locally advanced
- squamous cell carcinoma
- rna seq
- cystic fibrosis
- escherichia coli
- case report
- mesenchymal stem cells
- genome wide identification
- dna damage response
- endoplasmic reticulum stress
- free survival